A method for the differentiation of presynaptic inhibitors of adrenergic neurotransmitter release.

Injection of clonidine hydrochloride, 30 microgram/kg iv, or bretylium tosylate, 5 mg/kg iv, in pithed male spontaneously hypertensive rats inhibits the pressor responses to stimulation of the total sympathetic outflow, and enhances those to injected noradrenaline. The intravenous injection of d-amphetamine sulphate, 200 microgram/kg, reverses bretylium inhibition of the responses to sympathetic stimulation but not that of clonidine. Yohimbine, 10 microgram/kg/min iv on the other hand, reverses clonidine inhibition of the responses to sympathetic stimulation, but not that of bretylium. This pharmacological analysis provides a method for the differentiation of the mechanism of effect of two types of antihypertensive drug which act presynaptically to impair the release of the neurotransmitter from sympathetic nerves, viz., sympathetic neurone blocking agents (such as bretylium tosylate) and presynaptic alpha-adrenoceptor stimulants (such as clonidine hydrochloride).

Biologic properties of romazarit (Ro 31-3948), a potential disease-modifying antirheumatic drug.

The biologic effects of a new potential disease-modifying antirheumatic drug, romazarit (Ro 31-3948, 2-[[2-(4-chlorophenyl)-4-methyl-5-oxazolyl]methoxy]-2-methylpropio nic acid), have been investigated. In a 5-day adjuvant arthritis model, romazarit inhibited the development of hindpaw inflammation with a minimum effective dose of 30 mg kg-1. Plasma levels of the acute phase reactants seromucoid and haptoglobulin were also significantly reduced. Romazarit was equally effective in adrenalectomized animals, indicating that the compound is not acting via stimulation of the pituitary/adrenal axis. When the developing adjuvant arthritis was extended to 15 days romazarit showed dose-related improvements of all the symptoms of arthritis with a minimum effective dose of 25 mg kg-1. Romazarit caused a dose-dependent (range 20-250 mg kg-1) reduction in both the inflammatory and bony changes occurring during collagen arthritis in the rat, without any significant effect on anticollagen antibody titers except at the highest dose. Collagenase and prostaglandin E2 production in cultures of talus bones taken from rats with collagen arthritis were reduced by romazarit. In vitro romazarit was an extremely weak inhibitor of prostaglandin synthetase activity in both sheep seminal vesicle (IC50 6500 microM) and rat renal medulla (IC50 greater than 300 microM) cell-free preparations. Romazarit showed little or no activity in models of acute inflammation such as rabbit skin edema, carrageenan pleurisy or UV-induced erythema. In both acute and chronic tests romazarit displayed no ulcerogenic potential. In comparison with the structurally similar compound clobuzarit, hepatic changes such as increases in catalase and peroxisome proliferation-associated 80,000 mol.wt. protein were markedly less with romazarit. Clinical studies with romazarit are currently in progress.